Oxo-M and 4-PPBP induction of tenogenic differentiation of perivascular tendon stem cells

a perivascular tendon and stem cell technology, applied in the field of oxom and 4ppbp induction of tenogenic differentiation of perivascular tendon stem cells, can solve the problems of limited clinical use of ctgf as a tendon injury therapy, difficult clinical adoption and regulatory approval, and crucial barriers to cell transplantation, etc., to achieve more aligned collagen structure, improve healing, and reduce gaps

Active Publication Date: 2020-03-10
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]Studies described herein show the combination of Oxo-M and 4-PPBP can induce tenogenic differentiation of PTSCs; Oxo-M significantly increases PTSC expression of tenogenic markers tenascin-C, vimentin, and scleraxis after 1 week of treatment in vitro; 4-PPBP significantly increases PTSC expression of tenogenic markers collagen I and III after 1 week of treatment in vitro; and the combined administration of Oxo-M and 4-PPBP has synergistic effects on tenogenic differentiation and increases expression of tenogenic markers collagen I and II, vimentin, tenomodulin, and scleraxis to comparable or higher levels than CTGF stimulation.

Problems solved by technology

Despite being a valid approach, cell transplantation has encountered crucial barriers in therapeutic translation, including immune rejection; pathogen transmission; potential tumorigenesis; issues associated with packaging, storage, and shipping; and difficulties in clinical adoption and regulatory approval.
While connective tissue growth factor (CTGF) has been shown to induce PTSCs to differentiate into tendon cells and helps to recruit PTSCs to the site of injury following tendon rupture, the clinical use of CTGF as a therapy for tendon injury may be limited by the many challenges typically associated with biologics.
Despite these promising results, however, the clinical use of CTGF as a therapy for tendon injury may be limited by the many challenges typically associated with biologics, which include high cost, immunogenicity, and the necessity for complex delivery systems.

Method used

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  • Oxo-M and 4-PPBP induction of tenogenic differentiation of perivascular tendon stem cells
  • Oxo-M and 4-PPBP induction of tenogenic differentiation of perivascular tendon stem cells
  • Oxo-M and 4-PPBP induction of tenogenic differentiation of perivascular tendon stem cells

Examples

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example 1

[0141]The following example shows a combination of Oxo-M and 4-PPBP induces tenogenic differentiation of perivascular tendon stem cells.

[0142]Perivascular tendon stem cells (PTSCs) were isolated from patellar tendons of 12 week-old Sprague-Dawley rats by sorting cells with strong surface expression of CD146, following established protocol (Lee, et al., 2015, supra). Culture-expanded PTSC (P2-3) were then treated with selected FAK and ERK1 / 2 agonists, including Oxotremorine M (Oxo-M) (1 mM), PPBP maleate (4-PPBP) (10 μM), Phenylarsine oxide (PAO) (2 μM), and [Tyr4]-Bombesin (BOM) (10 nM), and SKF-83959 (20 μM). A single concentration was tested for each molecule as a first screening study. After 1 week, tendon-related mRNA expressions, including collagen I and III, tenascin-C (Tn-C), vimentin (VIM), tenomodulin (Tnmd), and scleraxis (Scx), were measured.

[0143]Results showed that Oxo-M provided significant increases in Tn-C, VIM, and Scx, while 4-PPBP elevated expressions of COL-I and...

example 2

[0147]This Example shows that delivery in vivo of a combination of Oxo-M and 4-PPBP in a rat tendon defect model showed improved tendon healing. The animal model was used to study the in vivo response and development of these tissues from endogenous cells stimulated by Oxo-M and 4-PPBP delivery.

[0148]This study was designed to investigate effect of Oxo-M and 4-PPBP on tendon healing. Animals were given Oxo-M alone (1 mM), 4-PPBP alone (10 μM), and a combination of Oxo-M (1 mM)+4-PPBP (10 μM) along with fibrin gel as a vehicle after patellar tendon transection. Fibrin alone served as a vehicle control. Multiple time points (1 and 2 weeks) were selected to follow up the process of healing and remodeling of tendon. Tissue healing, matrix formation and remodeling, and functional restoration were examined using histology, immunohistochemistry, and mechanical testing (tensile) as per prior methods (Lee, et al., J. Clin. Invest. 120:3340-3349, 2010; Lee, et al., Lancet 376:440-448, 2010; L...

example 3

[0161]This Example shows that delivery in vivo of a combination of Oxo-M and 4-PPBP in a rat supraspinatus tendon injury model showed improved tendon healing. The animal model was used to study the in vivo response and development of these tissues from endogenous cells stimulated by Oxo-M and 4-PPBP delivery.

[0162]This study was designed to investigate effect of a combination of Oxo-M (1 mM)+4-PPBP (10 μM) along with fibrin gel as a vehicle after supraspinatus tendon transection. Fibrin alone served as a vehicle control. Four weeks post-op was selected to follow up the process of healing and remodeling of tendon. Tissue healing, matrix formation and remodeling, and functional restoration were examined using histology as per prior methods (Lee, et al., J. Clin. Invest. 120:3340-3349, 2010; Lee, et al., Lancet 376:440-448, 2010; Lee, et al., Sci. Transl. Med. 6(266):266ra171, 2014; Lee et al., 2015, supra).

[0163]The study was designed as follows:

[0164]1. Rat supraspinatus tendon was t...

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Abstract

Provided herein are compositions including oxotremorine (e.g., oxotremorine methiodide or Oxo-M) and 4-PPBP (e.g., 4-PPBP maleate). Also provided are methods of treating a connective tissue defect in a subject with oxotremorine and 4-PPBP. In addition, provided are scaffolds and methods of making same that include multiple fibers that include Oxo-M, 4-PPBP, and optionally icariin or kartogenin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation-in-part from PCT / US17 / 22751 filed Mar. 16, 2017 which claims the benefit of U.S. Provisional Application Ser. No. 62 / 309,050, filed Mar. 16, 2016 and claims priority under 35 USC 119 and 120 to the foregoing applications.[0002]The present application also claims the benefit of U.S. Provisional Application No. 62 / 668,582 filed May 8, 2018, which are incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0003]Current stem cell-based strategies for tissue regeneration involve ex vivo manipulation of these cells to confer features of the desired progenitor population. Despite being a valid approach, cell transplantation has encountered crucial barriers in therapeutic translation, including immune rejection; pathogen transmission; potential tumorigenesis; issues associated with packaging, storage, and shipping; and difficulties in clinical adoption and regulatory approval.[0004]Perivascu...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/4015A61P31/00A61L27/56A61K9/16B33Y80/00A61P37/06A61K9/00A61K31/196A61L27/54A61L27/18
CPCA61L27/54A61K9/1635C08L67/04A61K9/0019A61K31/4015A61K9/16A61P31/00A61L27/56A61K9/0024A61P37/06A61K31/196A61L27/18B33Y80/00A61L2300/412A61L2300/622A61K9/0097A61K9/14A61K9/2022C04B2111/00181
Inventor LEE, CHANG HUNTARAFDER, SOLAIMANCHEN, ESTHER
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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